The early detection of cancer using medical imaging equipment requires the ability to detect small lesions or to delineate the boundaries of lesions that have properties close to those of the surrounding normal tissue. The measure of the smallest object visible with a given contrast is called the contrast detail resolution of the imaging system. Contrast-detail resolution and other performance tests of a medical imaging system are performed with objects called phantoms. A phantom with a variability of size and contrast objects is required for the evaluation of the contrast-detail resolution of the system. Such phantoms are commercially available for use with X-ray computed tomography, ultrasound imaging systems, and nuclear magnetic resonance imaging systems but are not generally available for the ultrasound and magnetic resonance elasticity imaging systems used in elastography. Elastography is a relatively recent technology directed at the early detection of tumors. Over the last decade, elastography has been recognized as having great potential as a tool for breast and prostate cancer diagnosis. In addition it may also play an important role in areas such as monitoring tumor ablation therapy and intravascular plaque classification. Presently, there is a great need for temporally stable heterogeneous phantoms to enable vigorous development and testing of elastographic hardware and software.
Elastography is the investigation of tissue elasticity using ultrasound methods. In ultrasound elastography (USE), an axial stress is applied to a tissue and the resulting strain of the tissue is determined from the change in the ultrasound echo signals before and after the application of the stress. With USE, a sample of tissue can be characterized by mapping out the local elastic strain of the analyzed tissue. The resulting mapping is called an elastogram. Hard tumor material will show less strain than softer tissues and this contrast between the elastic properties is picked up on an elastography image. The technique has the advantage of adding new diagnostic information to conventional ultrasound imaging.
Magnetic Resonance Elastography (MRE) is a particularly sensitive technique that couples the power of nuclear magnetic resonance imaging with the complementing information of elastography. There are two primary forms of MRE, harmonic MRE and quasistatic MRE. In harmonic MRE tissues are exposed to a deforming force at a frequency of 50-1000 Hz, generating longitudinal and shear waves throughout the tissue. In this method, an oscillating magnetic field gradient is used to induce spin phase change in proportion to the amplitude of the tissue motion. The tissue motion, or deformation, is measured by use of a phase contrast magnetic resonance technique and displayed in the form of an image. The quasistatic technique uses very low deformation frequencies between 0 and 1 Hz. In this method, wave propagation can be assumed to be negligible, with the tissue in an approximate state of static stress.
In addition to mimicking the elastic properties of soft tissue, the ideal tissue mimicking material for use in USE should have the same ranges of speeds of sound, attenuation coefficients, and backscatter coefficients as soft tissue. These parameters should be controllable in the manufacturing process of the phantom material, and their variation within the range of room temperatures should be small. Speeds of sound in human soft tissues vary over a fairly small range with an average value of about 1540 m/s. The speed of sound in fat is thought to be about 1470 m/s. The amplitude attenuation coefficients appear to vary over the range from 0.4 dB/cm to about 2 dB/cm at a frequency of 1 MHz in these tissues. The frequency dependencies of the attenuation coefficient of some soft tissues have been studied and, typically, it has been reported that the attenuation coefficient is approximately proportional to the ultrasonic frequency in the diagnostic frequency range of 1 to 10 MHz. An exception is breast fat, in which the attenuation coefficient is proportional to the frequency to the 1.7 power. This is discussed in F. T. D'Astous and F. S. Foster, “Frequency Dependence of Attenuation and Backscatter in Breast Tissue,” Ultrasound in Med. & Biol., Vol. 12, pp. 795-808 (1986).
For use in elastography, the tissue mimicking materials must exhibit the same Young's modulus as that of the tissue being mimicked. The Young's modulus varies significantly from tissue to tissue. Krouskop et al., have reported in vitro values for the Young's moduli (E) for normal and abnormal breast and prostate tissues using precompression and low frequency superimposed sinusoidal loading. At 5% precompression in breast and 4% in prostate cases, E ranged from 18±7 kPa for breast fat through 241±28 kPa for prostate cancer. The Young's modulus for normal breast glandular tissue was found to be approximately 30 kPa and the Young's modulus for invasive and infiltrating ductal carcinoma was around 100 kPa.
Phantoms for use in MRE should also possess nuclear magnetic resonance properties reflective of those found in human soft tissues. Soft tissues exhibit T1's ranging from about 200 milliseconds (ms) to about 1200 ms and T2's from about 40 ms to about 200 ms. Typical values for the ratio T1/T2 lie between about 4 and about 10 for soft tissues. For a given soft tissue parenchyma, T1 in particular can exhibit a significant dependence on frequency as well as temperature.
Each of the above-mentioned parameters should be controlled in order to provide the desired range of values in the manufacturing process of the phantom, and should agree at all frequencies in the clinical ultrasound range of 1-10 MHz. In addition, the materials should possess long-term stability over periods of months or years with respect to the elastic, ultrasound, and magnetic resonance properties, and with respect to geometries, such as inclusion size and shape. Moreover, if the phantom includes inclusions of materials within the surrounding matrix which have different elastic, ultrasound and magnetic resonance properties than the surrounding matrix, these inclusions must be stable over time in both size and shape and in physical and chemical properties.
Materials which have been proposed for use in elastography phantoms to mimic soft tissues include homogeneous gels of gelatin and homogeneous gels of agar. The gelatin phantoms typically include a paraldehyde or formaldehyde crosslinking agent. The Young's modulus values for such phantoms depend on the dry weight of agar or gelatin in the gels, and in the case of gelatin, on the concentration of the formaldehyde or paraldehyde used to crosslink the materials. Such phantoms have been in use as ultrasound phantoms for many years. These materials suffer from several drawbacks. First, homogeneous agar gels bond only weakly together, therefore an agar inclusion will not be strongly bonded to its agar surroundings in a phantom. In addition agar gels are brittle and fracture at modest strains. In contrast, homogeneous gelatin gels possess durable inclusions that bond well to gelatin surroundings. However, it is very difficult to produce stable elastic contrast in these phantoms because the inclusions and the surrounding materials are made from gelatin having varying dry weight concentrations of gelatin and formaldehyde, and there is a strong tendency for the materials to approach a uniform concentration of gelatin and formaldehyde over time through diffusion. In addition, gelatins cannot be made to possess adequately large T1/T2 ratios to simulate soft tissues.
Another phantom that has been proposed for use in elastography imaging systems is a heterogeneous phantom having a gelatin section and an agar component. Unfortunately, the Young's modulus for the agar component in such phantoms was found to increase by a factor of 6 for strains between about 2% and 7%. It has been found that the Young's moduli of normal fat, breast and prostate parenchyma exhibit only a small dependence on strain over similar strain ranges. Thus, for strains of less than about 10%, it does not appear that agar by itself is a suitable material for mimicking normal breast or prostate tissue.
Polyvinyl alcohol gels have also been investigated regarding their suitability for magnetic resonance elastography phantoms. However, these materials do not possess long-term stability and are significantly stiffer than biological soft tissue.
Silicone rubber has also been tested for use with magnetic resonance elastography. Unfortunately, the speed of propagation of sound in silicone rubber is too low for this material to be a realistic option for ultrasound elastography studies.
Other phantoms for use in elastography include phantoms made from mixtures of agar and gelatin. One such phantom is made from 8% gelatin and between 1 and 3% agar, based on the dry weight of the materials, in the absence of a crosslinking agent. The Young's moduli of these materials are significantly temperature dependent at temperatures between 5° C. and 40° C. and the materials do not possess long-term stability with respect to shape and physical properties.
A phantom of this type is described in U.S. Pat. No. 5,312,755 to Madsen et al. This patent discloses a tissue mimicking NMR phantom that utilizes a base tissue mimicking material which is a gel solidified from a mixture of animal hide gelatin, agar, water and glycerol. The amount of glycerol can be used to control the T1. The preferred base material included a mixture of agar, animal hide gelatin, distilled water (preferably deionized), glycerol, n-propyl alcohol, formaldehyde, and p-methylbenzoic acid. The contrast-detail resolution phantom could include inclusions which have NMR properties which differ from the base tissue mimicking material. Differences in contrast between the surrounding base material and the spherical inclusions could also be obtained by the use of a solid such as powdered nylon added to the base material and the inclusions that has little NMR response but displaces some of the gelatin solution, decreasing the apparent 1H density to the NMR instrument.
Phantom materials composed of water based agar gels doped with MnCl2 to control T1 for use in conventional magnetic resonance imaging systems have been reported. R. Mathur-DeVre, et. al., “The Use of Agar as a Basic Reference for Calibrating Relaxation Times and Imaging Parameters,” Magn. Reson. Med., Vol. 2, 1985, p. 176. Agar gels doped with CuSO4 have also been reported. M. D. Mitchell, et al., “Agarose as a Tissue-Equivalent Phantom Material for NMR Imaging,” Magn. Reson. Imag., Vol. 4, 1986, p. 263.
A phantom material consisting of mixtures of agar gel and animal hide gel in which CuSO4 was used to lower T1 for use in conventional magnetic resonance imaging has also been reported. Unfortunately, a long-term instability manifested itself in that a steady, very slow rise in T1 was observed over a period of months. This instability precludes the use of this material in magnetic resonance phantoms. The rise in T1 was perhaps due to the slow formation of metal-organic complexes, removing the Cu++ paramagnetic ions. See J. C. Blechinger et al., “NMR Properties for Tissue-Like Gel Mixtures for Use as Reference Standards or in Phantoms,” Med. Phys., Vol. 12, 1985, p. 516 (Abstract). More recently, the problem of gradual increase in T1 in the agar, animal hide gel, Cu++SO4−− gel has been eliminated by addition of the chelating agent EDTA (ethylenediaminetetraacetic acid). This stable material is excellent for use in MRI phantoms. See J. R. Rice, et al., “Anthropomorphic 1H MRS Head Phantom,” Med. Phys., Vol. 25, 1998, pp. 1145-1156.
Further ultrasound and MRI phantoms are illustrated in U.S. Pat. Nos. 6,238,343 and 6,318,146.